Notice that the title says ‘Causes’. There’s little doubt that “chronic fatigue syndrome” can be produced in a variety of ways. The definition is too broad and the responses to treatments are too variable for this disease not to have several, perhaps even numerous, causes.

complex causes of chronic fatigue syndrome

Multiple theories abound regarding the cause of chronic fatigue syndrome. A heterogeneous population suggests several could be correct.

That said, some common findings have emerged; most ME/CFS researchers appear to believe ME/CFS is a multi-systemic disorder involving the autonomic, immune, and neuroendocrine systems.

Triggering Chronic Fatigue Syndrome (ME/CFS)

Infection, injury, physical or psychological stress, toxin exposure, vaccination, being in intensive care, and other stressful events have all been reported to trigger ME/CFS-like states. Studies have documented the role pathogens including Epstein-Barr virus (infectious mononucleosis/glandular fever), Coxiella burnetii (Q fever), Ross River virus (epidemic polyarthritis), Giardia lamblia (giardiasis), SARS-CoV-1, SARS-CoV-2 (long COVID) can play  in triggering ME/CFS.

Study findings suggest that an overly strong immune response (high cytokine levels) to an infection, and severe symptoms may be able to predispose people with colds to come down with ME/CFS. The COVID-19 pandemic has shown, however, that even asymptomatic infections can trigger long COVID in susceptible individuals.

The Central Nervous System

Abnormal patterns of brain activity, reduced brain blood flows and brain volume, small brain lesions, high brain lactate levels, and others suggest areas of the brain involved in the stress response, energy production, concentration, motivation, fatigue, and pain are damaged in chronic fatigue syndrome (ME/CFS).

Recent findings of widespread neuroinflammation have sparked much interest and could explain much. Areas of particular interest in the brain include the brainstem, the hypothalamus, the basal ganglia, the prefrontal cortex, insula, orbitofrontal cortex, and anterior cingulate, and the connections between these regions.  Central sensitization is clearly contributing to the pain and fatigue experienced.

Immune Defects

The flu-like symptoms chronic fatigue syndrome (ME/CFS) patients often experience at the diseases onset has made the immune system an important research emphasis. Several immune abnormalities could contribute to the problems patients face. Many immune studies, however, have produced inconsistent findings.

  • Natural Killer (NK) and T-cell Dysfunction – NK dysfunction is consistently found and recent reports suggest a similar dysfunction may occurs in the T-cells.
  • Th1/Th2 Imbalance – There are two general branches (Th1/Th2) of the immune system. Some patients appear to have an over activation of the anti-inflammatory (Th2) branch and an under activation of the pro-inflammatory (Th1) branch of the immune system. This could cause increased rates of allergy and sensitivity on the one hand and difficulty fighting off pathogens on the other.
  • Th17 – recent studies suggest the Th17 system regulating inflammation and autoimmune processes may be affected.
  • Autoimmune – A few studies suggest that autoantibodies associated with adrenergic and other receptors are increased.
  • Immune exhaustion – some studies suggest that immune exhaustion may be present in patients with longer duration illnesses. This immune exhaustion takes the form of reduced NK and T-cell activity and immune factor production. A similar process may be occurring in fibromyalgia.

An Undiagnosed Chronic Infection

Some researchers and doctors propose ‘atypical’ herpesvirus  (HHV6, EBV, Enterovirus) infections are triggering an immune response that is causing the symptoms of ME/CFS.  Others believe a difficult to diagnose brain infection (HHV6A) may be present.

Many cases of chronic fatigue syndrome start with an infection

With infectious onset being common, interest in pathogens is high. We should know much more about pathogens and ME/CFS by 2014.

Increased Sympathetic and Decreased Parasympathetic Nervous System (SNS/PNS) Activation

Low heart rate variability is common in both ME/CFS and fibromyalgia.  Narrowed blood vessels and low blood volume associated with increased SNS activity could result in reduced brain and muscle blood flows, produce heart abnormalities under stress, and other problems Reduced PNS activity could also contribute to unrefreshing sleep and digestive issues.

Metabolic/Mitochondrial Issues

Two-day exercise studies indicate that many people with ME/CFS are unable to duplicate their energy production on the second day of the test. This unusual problem – seen thus far only in chronic fatigue syndrome – suggests that the energy production process in ME/CFS is “broken”.  Some studies point to mitochondrial dysfunction as a possible culprit. Other studies suggest that the cells in people with ME/CFS could exist in a state of hibernation. Metabolomic studies point to the possible existence of a hypometabolic state in the disease characterized by increased utilization of amino acids for energy.

Impaired Stress Response

Impaired hypothalamic-pituitary-adrenal (HPA) axis functioning (apparently at the hypothalamus) and reduced cortisol levels are present in some patients. Chronically impaired HPA axis functioning could set the stage for a Th2 immune imbalance that inhibits the ability to fight off pathogens.

Gut Flora Imbalance and Bacterial Translocation (Leaky Gut)

Some studies suggest that altered gut flora and weakened boundary junctions may be occurring and are may be worsened by exertion. Weakened gut boundary junctions that allow movement of gut materials into the blood could spark an immune response and might even be triggering the disease in some cases.


Some studies suggest a strong genetic component is present in both ME/CFS and FM. Several gene mutation studies have found increased rates of neuro-endocrine and immune mutations.

Psychological Issues

Numerous studies indicate that pre-existing mood disorders do not increase the risk of getting ME/CFS, and the presence of a mood disorder does not affect the symptoms associated with ME/CFS.

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